The role of mTORC2 in cancer cell metabolism PROJECT SUMMARY Metabolic reprogramming is a hallmark of cancer. Mutations in growth factor receptor signaling pathways promote tumor growth by altering the uptake and utilization of nutrients. De novo synthesis of lipids is a critical aspect of this process, providing necessary lipids for membrane biogenesis and signal transduction. Currently, there is a major gap in our knowledge about how oncogenic signaling regulates the synthesis of specific lipids to cause tumor growth, and by what mechanisms. this RO1 grant (NS 73831), we have demonstrated that Through studies supported by the first five years of the mechanistic target of rapamycin (mTORC2), a critical mediator of growth factor receptor signaling, reprograms tumor cellular metabolism, potently stimulating the growth of the highly lethal brain cancer glioblastoma (GBM) and causing resistance to almost all current treatments. Specifically, our preliminary studies indicate that mTORC2 drives nutrient flux into lipogenic pathways and boosts the synthesis of specific lipids to drive tumor growth by regulating the levels and/or activities of key rate limiting enzymes. These data reveal a landscape of new, potentially druggable targets. However, before these mechanisms can be applied to inform the development of new therapies, a number of urgent questions must be answered. How does mTORC2 regulate GBM nutrient uptake and utilization and shift it towards the synthesis of specific lipids in cancer? What are the signaling, biochemical and transcriptional mechanisms and how do they drive tumor growth and drug resistance? Are they druggable? This proposal is designed to test the hypothesis that mTORC2 promotes GBM growth and drug resistance by driving lipogenesis and remodeling the composition of specific signaling lipids. Our goal is to understand the mechanisms most critical for breaking down a major barrier to developing more effective treatments. In aim 1, we propose a set of experiments that will extend our metabolic analyses into patient-derived GBMs in vivo, to determine how mTORC2 controls the synthesis of specific phospholipids and sphingolipids to drive GBM growth and drug resistance, and to identify the signaling, biochemical and transcriptional mechanisms by which mTORC2 controls the key enzymes that regulate this process. In aim 2, we will determine how mTORC2 controls the uptake and utilization of nutrients towards the synthesis of these specific lipids. In aim 3, we will identify and develop CNS-penetrant small molecules that target mTORC2-dependent metabolic reprogramming and evaluate their therapeutic potential. The proposed studies will generate a deeper understanding of the role of mTORC2 in cancer cell metabolism and will generate a landscape of previously unappreciated metabolic vulnerabilities that can be targeted by brain penetrant compounds, potentially leading to better GBM treatments